The rising prevalence of type 2 diabetes (T2D) is a major public health concern worldwide. It is clear that both genetic and environmental factors contribute to T2D. Known genetic variants account less than 10% of the risk for T2D predisposition. Evidence from human epidemiology and animal studies show that fetal nutrient environmental factors (e.g. placental insufficiency) provide additional susceptibility to T2D. We and others have shown that maternal low-protein diet throughout pregnancy (LP0.5) causes intrauterine-growth restriction (IUGR), a critical factor known to predispose offspring to T2D, by causing long-term consequences in ?-cell mass and function. Impaired placental growth and function are major causes of IUGR. mTOR, a nutrient-sensor kinase, couples signals from nutrients (e.g. amino acids)) and growth factors to promote cellular growth of an organism. Reduced mTOR signaling is correlated to decrease fetal placental function such as amino acid transport in human and rodent models of IUGR. By using multiple murine models, this R03 grant expands the K01 award and determine the requirement of fetal placental mTOR signaling in the developmental programming of ?-cell mass and function. We will test the hypothesis that changes in placental mTOR activity is sufficient to alter developmental programming of ?-cell dysfunction in the offspring with the following 2 aims: 1: Determine ?-cell mass and insulin secretion function in islets with placental loss or gain-of- function mTOR signaling; and 2: Identify the mechanisms of how placental mTOR signaling induces developmental programming of ?-cell mass and function in the offspring. The impact of these studies will show definitively the independent impact of placental mTOR signaling on ?-cell mass development and function programming in the offspring. We will identify specific placental factors that will yield novel insights into the mechanisms whereby mTOR regulates fetal nutrients. Finally, this grant will illustrate the translational relevance of placental mTOR as a biomarker to identify individuals at risk for T2D, thereby advancing clinical care.